tbuckley/cabot-search huggingface dataset:
Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial
Authors: Tim H. Brümmendorf, Jorge E. Cortes, Dragana Milojkovic, Carlo Gambacorti-Passerini, Richard E. Clark, Philipp le Coutre, Valentin Garcia-Gutierrez, Charles Chuah, Vamsi Kota, Jeffrey H. Lipton, Philippe Rousselot, Michael J. Mauro, Andreas Hochhaus, Rafael Hurtado Monroy, Eric Leip, Simon Purcell, Anne Yver, Andrea Viqueira, Michael W. Deininger
Journal: Leukemia (2022)

This analysis from the multicenter, open-label, phase 3 BFORE trial reports efficacy and safety of bosutinib in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) after five years' follow-up. Patients were randomized to 400-mg once-daily bosutinib (n = 268) or imatinib (n = 268; three untreated). At study completion, 59.7% of bosutinib- and 58.1% of imatinib-treated patients remained on study treatment. Median duration of treatment and time on study was 55 months in both groups. Cumulative major molecular response (MMR) rate by 5 years was higher with bosutinib versus imatinib (73.9% vs. 64.6%; odds ratio, 1.57 [95% CI, 1.08-2.28]), as were cumulative MR4 (58.2% vs. 48.1%; 1.50 [1.07-2.12]) and MR4.5 (47.4% vs. 36.6%; 1.57 [1.11-2.22]) rates. Superior MR with bosutinib versus imatinib was consistent across Sokal risk groups, with greatest benefit seen in patients with high risk. Treatment-emergent adverse events (TEAEs) were consistent with 12-month data. After 5 years of follow-up there was an increase in the incidence of cardiac, effusion, renal, and vascular TEAEs in bosutinib- and imatinib-treated patients, but overall, no new safety signals were identified. These final results support 400-mg once-daily bosutinib as standard-of-care in patients with newly diagnosed CP CML.This trial was registered at www.clinicaltrials.gov as #NCT02130557.
Induction mortality (IM) of acute myeloid leukemia (AML) patients treated with purine analogues-cytarabine-anthracycline at a general hospital.
Authors: Adan Rios, Binoy Yohannan, Frances Natalia Cervoni-Curet
Journal: Journal of Clinical Oncology (2022)

e19019 Background: Cytarabine-anthracyclines (7+3) induction chemotherapy (IC)) has been the mainstay therapy for over four decades and it remains the standard AML IC regimen internationally. Triplet IC using purine analogues (fludarabine/cladribine) in combination with cytarabine and idarubicin (FIA/CLIA) is superior to the standard 7+3 regimen, but challenging to administer in general hospital settings due to myelosuppression. We reviewed AML IM rate in patients induced with (fludarabine/cladribine) combined with cytarabine and idarubicin (FIA/CLIA) at Memorial Hermann Hospital, Texas Medical Center (MHH at TMC). Patients and Methods: Of 44 AML reviewed records from January 2013 to January 2022, 40 received 5 days FIA/CLIA IC, and four 3-4 days due to age and comorbidities. For clinical characteristics see Table. Results: Median age was 51.5 years (range: 18-68). Three died before assessment. After 1 cycle the composite CR (CR+ CR i) was 82.9% (34/41) and 87.8% (36/41) after 2 cycles. MRD negative composite CR was 92%. Four patients had adverse risk cytogenetics and primary induction failure (modified FIA). 37% had febrile neutropenia. 25% had bacteremia with 15% requiring ICU admission and 4% mechanical ventilation. The 30-day induction mortality was 9%. Conclusions: FIA/CLIA has a higher CR rate than ‘3+7’ (which historically is 60%). The 30-day induction mortality in non-academic centers is about 30%. Given the fact that in AML achieving a CR is the most important factor to improve survival, with adequate treatment expertise, triplet IC regimen can be safely administered with a low induction mortality. [Table: see text]
Perioperative chemotherapy with mFOLFOX6 or CAPOX for patients with locally advanced colon cancer (OPTICAL): A multicenter, randomized, phase 3 trial.
Authors: Huabin Hu, Meijin Huang, Yunfeng Li, Ziqiang Wang, Xiaozhong Wang, Ping Liu, Ruyi Zhang, Hao Zhang, Zhongcheng Huang, Haiping Pei, Yongming Zeng, Jiajun Lai, Wenbin Chen, Jiansi Chen, Zhijie Ding, Hongbo Wei, Qingwen Xu, Jigui Chen, Jianping Wang, Yanhong Deng
Journal: Journal of Clinical Oncology (2022)

3500 Background: Adjuvant chemotherapy is the recommended standard treatment for resected stage III and high-risk stage II colon cancer, but disease recurrence remain common. Perioperative chemotherapy has proved effective in several tumors, but not in colon cancer. We aimed to assess whether perioperative chemotherapy could improve outcomes in patients with locally advanced colon cancer. Methods: In this multicenter, randomized, phase 3 trial, participants were recruited from 28 hospitals in China. Eligible patients were aged 18-75 years, had a colon adenocarcinoma, with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4 assessed by CT). Patients were randomly assigned (1:1) to either the experimental group or standard of care group, stratified by center, cT stage, and cN stage. The experimental group received 3 months of neoadjuvant chemotherapy with mFOLFOX6 or CAPOX, then surgery, then 3 months of adjuvant chemotherapy. The standard of care group received immediate surgery, and optional adjuvant chemotherapy (per physician’s discretion according to pathological stage ). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Results: Between January 6, 2016, and April 3, 2021, 752 patients were enrolled and randomly assigned to a treatment, of whom 744 were eligible (371 in the experimental group; 373 in the standard of care group). At a median follow-up of 32.5 months (IQR 19.2-45.7), 3-year disease-free survival rates were 78.7% (95%CI 73.8-83.5) in the experimental group and 76.6% (95%CI 71.8-81.4) in the standard of care group (stratified HR 0.83, 95%CI 0.60-1.15; p = 0.138). A pathological complete response was achieved in 26 (7%) of 371 patients in the experimental group. 69 (19%) patients in the experimental group had low pathological disease stage (pT0-2N0) compared with 16 (4%) of 373 in the standard of care group (p &lt; 0.0001). 3-year overall survival rates were 94.9% (95%CI 92.1-97.7) in the experimental group and 88.6% (95%CI 84.6-92.5) in the standard of care group (stratified HR 0.47, 95%CI 0.25-0.87; p = 0.012). The post hoc subgroup analyses revealed perioperative chemotherapy induced an increase in disease-free survival in female patients (HR 0.54, 95%CI 0.31-0.83; p = 0.025). Conclusions: In patients with locally advanced colon cancer, perioperative chemotherapy with mFOLFOX6/CAPOX increased chance of pathological downstaging, but did not improve disease-free survival compared with standard of care. Clinical trial information: NCT02572141. [Table: see text]
ATRT-16. Mechanisms of myeloid cell-induced resistance in AT/RT
Authors: Alina Disch, Viktoria Melcher, Carolin Walter, Marta Interlandi, Natalia Moreno, Flavia W de Faria, Monika Graf, Martin Hasselblatt, Thomas K Albert, Kornelius Kerl
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Atypical teratoid/rhabdoid tumor (AT/RT) is a primary pediatric tumor entity of the central nervous system showing intra- and intertumoral heterogeneity concerning the molecular landscape and cellular composition. Myeloid cells are considered key orchestrators of the immunological tumor microenvironment (TME) of AT/RT. Tumor-infiltrating CD68+ macrophages favor chemotherapy resistance and recurrence, and are consequently related to a poor patient outcome. METHODS: Using single-cell RNA sequencing (scRNA-seq) of human and murine AT/RT samples, multiplex immunohistochemistry, depletion of myeloid cells in mouse models and advanced cell culture models for myeloid tumor cell communication, we obtained deeper mechanistic insight into these cell-cell interactions. RESULTS: Infiltrating CD68+ macrophages interact with AT/RT tumor cells generating intermediary hybrid-like cells with autonomous communication properties, increasing the cell heterogeneity of AT/RT. By depletion of myeloid cells in AT/RT mouse models followed by scRNA-seq of tumor and non-tumor samples, we demonstrated that tumor formation is hindered. Furthermore, we give mechanistic insights into how myeloid cells contribute to tumorigenesis. IN CONCLUSION: the dynamic and extensive interactions between tumor cells and myeloid cells do not only potentiate cellular heterogeneity but might also induce cellular plasticity associated with the acquisition of resistance to chemotherapy and seem to be essential for AT/RT development.
Ethical challenges with CAR T slot allocation with idecabtagene vicleucel manufacturing access.
Authors: Taxiarchis Kourelis, Radhika Bansal, Krina K. Patel, Jesus G. Berdeja, Noopur S. Raje, Melissa Alsina, Adam D. Cohen, David Samuel DiCapua Siegel, Sham Mailankody, Myo Htut, Surbhi Sidana, Sarah A. Holstein, Andrew Cowan, Nina Shah, Peter Leif Bergsagel, Sikander Ailawadhi, Yi Lin
Journal: Journal of Clinical Oncology (2022)

e20021 Background: CAR T cell therapies are FDA approved for patients with triple refractory multiple myeloma (MM) and &gt;4 lines of therapy. The median survival of this is group is less than 12 months so salvage therapies need to be implemented quickly. Real-world access to CAR T remains challenging due to supply chain limitations impacting manufacturing. The goal of this study was to evaluate how centers are handling the challenges of CAR T slot allocation. Methods: MM CAR T physician leaders at each CAR T treatment center certified for idecabtagene vicleucel across the US were surveyed. Results: We received responses from 15/20 centers. Summary of CAR T volumes and outcomes of patient on waitlists are shown in the table. The median time on the waiting list was 6 months with only 25% of patients receiving CAR T eventually. For patient selection, all centers reported using a committee of experienced CART physicians to ensure consistency. Selection committee included: primary MD (n=9), CAR T MD (n=12), social workers (n=3), CAR T RN (n=10), APP (n=2), pharmacists (n=2) and ethicists (n=1). To ensure transparency, centers have clear selection criteria (n=10), priority score (n=8) and selection timeline (n=11) . To ensure accountability, centers document priority scores (n=5) and have pre-specified criteria (n=9) for selection. Centers also reported using ethical principles for selection: a) equal treatment: time spent on waiting list (n=8); b) priority to the worst-off: limited therapeutic options (n=10), MM burden (n=7), ineligible for trials (n=2); c) maximize benefit: most likely to complete apheresis (n=8) or infusion (n=8) or achieve response (n=6) and d) social value: younger pts (n=2). Maximizing benefit was considered the most important criterion by 7 centers. Conclusions: More stringent GMP manufacturing requirements with FDA approved CAR T and real-world practice with broader patient demographics can present challenges to implementation of CAR T in standard of practice. Our study is the first attempt to evaluate and highlight existing issues with MM CAR T access and the variability and challenges in patient selection. Learning from other models of resource allocation (ex: UNOS) and sharing experience across centers can help providers optimize slot allocation to improve accrual. Increasing supplies of key reagents and novel manufacturing methods(eg: non-viral vectors and allogeneic CAR) could help overcome these limitations. [Table: see text]
The educational burden of disease: a cohort study
Authors: Magnus Nordmo, Jonas Minet Kinge, Bjørn-Atle Reme, Martin Flatø, Pål Surén, Jonathan Wörn, Per Magnus, Camilla Stoltenberg, Fartein Ask Torvik
Journal: The Lancet Public Health (2022)

Students with health disorders might be at risk of disengaging from education, which can reinforce socioeconomic inequalities in health. We aimed to evaluate the associations between 176 diseases and injuries and later school performance in Norwegian adolescents and to estimate the importance of each disorder using a novel measure for the educational burden of disease (EBoD).We used diagnostic information from government-funded health services for all Norwegian inhabitants who were born between Jan 1, 1995, and Dec 31, 2002, were registered as living in Norway at age 11-16 years, and were participating in compulsory education. School performance was assessed as grade point average at the end of compulsory education at age 16 years. We used a linear regression of school performance on disease in a fixed-effects sibling comparison model (113 411 families). The association (regression coefficients) between disease and school performance was multiplied by disease prevalence to estimate the proportional EBoD among 467 412 individuals participating in compulsory education.Overall, although most diseases were not meaningfully associated with grade point average (regression coefficients close to 0), some were strongly associated (eg, intellectual disability regression coefficients -1·2 for boys and -1·3 for girls). The total educational disease burden was slightly higher for girls (53·5%) than for boys (46·5%). Mental health disorders were associated with the largest educational burden among adolescents in Norway (total burden 44·6%; boys 24·6% vs girls 20·0%), of which hyperkinetic disorder contributed to 22·1% of the total burden (boys 14·6% vs girls 7·5%). Among somatic diseases, those with unknown causes and possibly mental causes were associated with the largest educational burden.The EBoD concept could provide a simple metric to guide researchers and policy makers. Because mental health disorders form a large component of the educational burden, investment in mental health might be particularly important for improving educational outcomes in adolescents.The Research Council of Norway.
Positive impact of academic center care on overall survival in malignant pleural mesothelioma (MPM): A National Cancer Database (NCDB) socioeconomic factor analysis.
Authors: Logan Roof, Wei Wei, James Stevenson
Journal: Journal of Clinical Oncology (2022)

8558 Background: MPM is a rare cancer with a poor prognosis. Median survival for untreated patients is 4-13 months, and for treated patients is 6-18 months. Despite asbestos regulations in the United States, annual deaths from MPM rose from 2,479 in 1999 to 2,597 in 2015. Given recent treatment advances, including improvements in multimodality therapy and the introduction of immunotherapy as a treatment option in the frontline setting, the impact that patient demographics and treatment factors have on survival outcomes for MPM requires further evaluation. Methods: We identified all patients with MPM in the NCDB from 2004 to 2017. Differences in demographic, disease, and treatment characteristics were assessed by year of diagnosis using Chi-square test. The effect of age, race, insurance status, income, distance to treatment center, and education level on overall survival (OS) was assessed by log-rank test. Results: There were 15,287 MPM diagnoses in the NCDB between 2004-2010 and 17,059 diagnoses between 2011-2017. OS improved between the two time periods, with median OS of 9.46 months (95% CI: 9.23-9.63) and 5-year OS rate of 8.3% (95% CI: 7.9-8.7%) in patients from 2004-2011 and median OS of 11.33 months (95% CI: 11.01-11.7) and 5-year OS rate of 12.4% (95% CI: 11.8-13.1%) in patients after 2011, despite an increase in stage IV disease in the latter group. Older patients (≥65 years-old), males, patients with stage IV disease, patients with government primary payer insurance, and patients from urban areas all had significantly worse OS. Patients without comorbidities and those treated at an academic center had significantly better OS. OS was found to significantly increase as both income and education level increase. Patients diagnosed after 2011 were significantly older, were more frequently female, had more stage IV disease, were more frequently treated at academic centers, more commonly had government primary payer insurance, and lived significantly further away from their treatment center. Patients’ time to treatment was significantly increased after 2011 (from 28 to 31 days). Conclusions: Socioeconomic factors play an important role in survival outcomes for patients with MPM. Many of these are linked with access to healthcare resources, which may increase the likelihood of evaluation at academic centers. For a rare malignancy such as mesothelioma, subspecialty care consisting of a comprehensive thoracic surgical evaluation and appropriate multimodality treatment are of great importance. Time to treatment increased during the study period yet OS improved, which our findings suggest are a result of an increase in evaluation and treatment at academic centers by providers skilled in delivering care to MPM patients.
Analysis of alopecia areata surveys suggests a threshold for improved patient-reported outcomes
Authors: Yael Renert-Yuval, Joel Correa da Rosa, Sandra Garcet, Ana B. Pavel, Jennifer Bares, Margot Chima, Jason E. Hawkes, Patricia Gilleaudeau, Mary Sullivan-Whalen, Giselle K. Singer, James G. Krueger, Emma Guttman-Yassky
Journal: British Journal of Dermatology (2022)

Although alopecia areata (AA) greatly impacts patients' quality of life (QoL), there is no adequate validation of AA-targeted QoL surveys in clinical trials, hindering sufficient representation of patient-reported outcomes.Better understanding of patient-reported outcomes may guide treatment goals and future clinical trials.In a recent randomized controlled trial testing dupilumab in AA, patients were administered the Alopecia Areata Quality of Life Index (AA-QLI) and the Alopecia Areata Symptom Impact Scale (AASIS) surveys, specifically evaluating QoL in patients with AA. An in-depth analysis was performed to assess the utility of these questionnaires in this patient population, both at baseline and after treatment, and to determine a threshold for improved patient-reported outcomes.While AASIS correlated with baseline Severity of Alopecia Tool (SALT) scores and with therapeutic response, AA-QLI showed no correlation with AA severity before or after treatment. Itch strongly correlated with serum IgE levels across both surveys. Using various approaches to estimate a discriminative threshold for decreased impact of AA on QoL (by AASIS) following treatment, a SALT score of 20 points or less post-treatment was associated with improved patient-reported outcomes, including both AA-related symptoms and items within the daily activities/feelings domain such as 'feeling sad' and 'feeling anxious or worry'.AASIS is better than AA-QLI to assess patient-reported outcomes. SALT ≤ 20 following treatment should be considered as a threshold for meaningful therapeutic outcome and as a clinical endpoint in future clinical trials for AA. What is already known about this topic? Alopecia areata greatly compromises quality of life, and affected patients have increased prevalences of depression, anxiety and social phobia. Despite the significant negative impact of the disease on patients' wellbeing, validation of targeted questionnaires in alopecia areata is lacking, and a therapeutic response threshold for improved patient-reported outcomes is unknown. What does this study add? This study investigated the utility of two different alopecia areata-targeted questionnaires - Alopecia Areata Quality of Life Index and Alopecia Areata Symptom Impact Scale (AASIS) - in a clinical trial setting. AASIS was found to correlate strongly with alopecia areata severity and clinical response. What are the clinical implications of this work? Patients with ≤ 20% scalp hair loss after treatment reported improvement in multiple quality-of-life items, suggesting this as a meaningful therapeutic outcome that may guide clinicians and improve the development of future clinical trials.
MEDB-90. Iron Imbalance Can Potentiate Cisplatin Response in Pediatric Medulloblastoma by Regulating Ferroptosis
Authors: Ranjana Kanchan, Naveenkumar Perumal, Parvez Khan, David Doss, Ramakanth Chirravuri Venkata, Ishwor Thapa, Raghupathy Vengoji, Jyoti Kaushal, Jawed Siddiqui, Mohd Wasim Nasser, Surinder Batra, Sidhartha Mahapatra
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, is a leading cause of childhood mortality. Of the four primary subgroups, patients with group 3 tumors have the poorest prognosis. Loss of chromosome 17p is a high-risk feature associated with poor outcomes in group 3 tumors. We recently elucidated the tumor suppressive properties of a novel miR, miR-1253, on the terminal end of 17p. In further exploring its anti-neoplastic effects, we discovered that miR-1253 can disrupt iron homeostasis, causing oxidative stress and inducing lipid peroxidation. These concurrent events are capable of triggering an iron-mediated form of cell death called ferroptosis. Notably, our in silico interrogation of ferroptosis regulator genes (FRGs) in group 3 tumors revealed high expression of genes associated with iron transport and glutathione metabolism. These included mitochondrial iron transporters and GPX4, a critical regulator of ferroptosis. Restoration of miR-1253 expression in group 3 cell lines resulted in specific downregulation of ABCB7, an iron-sulfur cluster exporter, and GPX4. Consequently, cytosolic and mitochondrial labile iron pools rose, glutathione levels declined, and mitochondrial oxidative stress and lipid peroxidation were induced. These events were recapitulated by ABCB7 knockdown and potentiated cell death. Treating miR-1253-expressing cancer cells with cisplatin, a group 3 MB chemotherapeutic agent with ferroptotic properties, further elevated oxidative stress, depleted glutathione levels, and augmented lipid peroxidation, with added inhibitory effects on cell viability and colony formation. Treatment with a ferroptosis inhibitor (ferrostatin-1) lead to recovery from the cytotoxic effects of this combination therapy. Our studies highlight a novel mechanism for group 3 MB pathogenesis via ferroptosis regulation and provide a proof-of-concept for exploiting group 3 MB tumor vulnerability to iron imbalance as a novel treatment strategy.